For the treatment of chronic illnesses or for continuous substitutive or prophylactic therapy there is a great need for depot formulations capable of releasing a medicine over an extended period of time with therapeutically relevant effectiveness.
These depot formulations can be administered in various ways, for instance orally, topically, inhalationally or parenterally.
For all pharmaceutical agents whose active concentrations should ideally remain uniform over a very long time, parenteral depots such as medicaments suitable for subcutaneous or intramuscular administration are of particular interest. This is all the more important when the pharmaceutically active substance is not adequately absorbed or degraded after enteral administration. These parenteral medications can be formulated for instance as microparticles or implants. Microparticles are of particular interest since because of their small size they permit the use of cannulas and are easily applied.
One major problem in the production of suitable depot formulations and especially of agents having a higher molecular weight such as peptides or proteins lies in the fact that their release often follows a discontinuous or multiphase pattern. To avoid that problem, attempts have been made to control the release profile of peptides. While the production of depot formulations such as microparticles offers only a limited number of possibilities, the properties of the depot formulations can be significantly modulated by modifying the polyesters on which these depot formulations are based.
For the production of suitable depot formulations, biodegradable polymers are of particular interest. Pharmacologically active substances are embedded in these polymer matrices and their release is regulated by the diffusion rate in the polymer as well as the polymer degradation rate. The characteristics of the polymer in terms of the pharmacon release and degradation rate thus determine to a very significant extent the quality of the pharmaceutical depot.
Biodegradable polyesters for embedding active substances on the basis of hydroxycarboxylic acids were described as early as 1973 in U.S. Pat. No. 3,773,919. Particular emphasis was given to polyesters based on lactic acid and glycolic acid, which after their in-vivo application are first hydrolized in nonenzymatic fashion into monomers and are then completely metabolized into CO2 and H2O.
However, the drawback of the polyesters described, when these are used in depot formulations and especially in microparticles, is that there is a strong initial burst of the active ingredient due to the erosion of the surface-bound agent, followed by a phase of severely reduced release, before a release of the agent through the degradation of the bulk of the polyester sets in. Since it is generally desirable for the active substance to be released in as linear a fashion as possible, the polyesters described in U.S. Pat. No. 3,773,919 lend themselves only to a rather minor extent to the production of depot formulations.
Another problem inherent in the polylactide glycolide polyesters (PLG polyesters) described in U.S. Pat. No. 3,773,919 is their slow degradation rate. Polyesters with a high molecular weight, often encountered in the production process, degrade only slowly and can lead to an accumulation of polyester residue as well as to active-substance inclusions in the depots for instance under the skin or in the muscle.
It is therefore particularly important to develop a biodegradable matrix material that can be formulated in a way that in the body it results in a linear release of the active substance over a specified period while at the same time being largely hydrolized.
One possibility to control both the release rate and the degradation rate of the depot concerned is to reduce the molecular weight of the polyester.
EP 058 481 describes the use of a mixture composed of PLG polyesters with different molecular weights. That process, however, results in a very heterogeneous, difficult-to-form polyester mixture that is, at best, only marginally suitable for producing microparticles containing the active substance by spray drying.
EP 299 730 describes the production of a biocompatible polyester by the ring-opening polymerization of D,L-lactide and glycolide, with the chain length controlled by adding lactic acid. Here, however, the depot formulations produced from the resultant PLG polyesters release the active substance in strongly sigmoid fashion, while displaying poor mechanical properties that complicate their processing into microparticles.
EP 407 617 describes the production of a PLG polyester with an elevated hydrolyzing rate by the ring-opening polymerization of D,L-lactide and glycolide. Modulation is accomplished by adding glycosides which in the polymerization reaction are bound to the repetitive glycolide-lactide backbone. While depot formulations based on these poly sters are suggested, they are not described.
EP 372 221 describes the continuous production of absorbable polyesters in an extruder. While it suggests the production of polyesters suitable for administering medicaments, it does not disclose such a process. For producing the variously desired viscosity levels it recommends “suitable additives” without, however, providing any indication relative to the nature of these additives.
It has therefore been the objective of this invention to introduce an absorbable polyester that permits a high active-substance content, leads in a pharmaceutical depot formulation to a linear release of the active substance and degrades at a rate in synchronism with the release of the active substance, thus avoiding any accumulation of the polyester in the body.
The invention has further been aimed at solving the upscaling problems associated with the production of absorbable polyesters by batch processing. It is a known fact that results obtained with a more limited synthesizing approach cannot be reproduced in large-volume syntheses, or inadequately at best, due to the thermodynamics involved.
According to the invention, this objective has been achieved by producing absorbable polyesters with the addition in the extruder of electrolyte-containing polyols and, in particular, of dextran sulfate.